The natural antibody repertoire is a segment of the immune system that is little understood, was early postulated to provide a first defense against specific infectious agents (Michael, J. G., 1969, Curr. Top. Microbiol. Immunol. 48:43-62), and has recently been the subject of increased interest and conjecture of a possible role in control of autoimmunity (Cohen, I. et al., 1986, Immunol. Today 2:363-364) or other phases of immunoregulation (Dighiero, G. et al., 1985, J. Immunol. 134:765). Natural antibodies frequently have been designated as those of lower affinity than their induced counterparts (see, e.g., Day, E. D. et al., J. Neuroimmunol. 13:143-158, 1986; Hoch, S. et al., J. Immunol. 136:892-897, 1986; Tongio, M. M. et al., Tissue Antigens 26:27-285, 1985).
Natural antibodies, in accordance with the long held and recently fortified hypothesis that the humoral immune system includes a repertoire of "natural" (Jerne, N. K., Proc. Natl. Acad. Sci. USA 41: 849, 1955) or "naive" (Berek, G. et al., Immunol. Rev. 105: 5-26, 1988) antibodies, not attributable to immune induction, are the subject of much speculation. The various characteristics attributed to that class of antibodies include: germ line configuration of VH and VL segments (Stollar, D. Mol. Immunol., 28:1339, 1991; Sanz, I. et al., J. Immunol. 142:4054, 1989), IgM of low affinity (Rodman, T. C. et al., Clin. Immunol. Immunopath. 57:430, 1990), secretion by CD5.sup.+ B-cells (Hayakawa, K. et al., Proc. Natl. Acad. Sci. USA 81:2494, 1984), polyreactivity (Casali, P. et al., Immunol. Today 10:364, 1989; Lymberi, P. et al., Eur. J. Immunol. 57:702, 1985) and presence in sera of all normal individuals with apparent quiescence until needed to provide "first line of defense" (Lymbori, P. et al., supra) against new infectious invaders.
Natural antibodies constitute a repertoire, usually IgM, occurring in sera of healthy children and adults, with no basis for assignment of antigen mediated induction (Jerne, N. K., Supra 41:849, 1955; Michael, J. G. et al., J. Exp. Med. 118:619, 1963; J. Boyden, S. V., Adv. Immunol. 5:1, 1966; Denis, K. A. et al., J. Exp. Med. 157:1170, 1983; Rodman, T. C. et al., Science 228:1211, 1985; Berek, C. et al., supra; Coutinho, A. et al., Cold Spring Harbor Symp. Quant. Biol. 54:159, 1990; Avrameas, S., Immunol. Today 12: 154, 1991). Natural antibodies have been frequently characterized as polyspecific (Guilbert, B. et al., J. Immunol. 128:2779, 1982; Martini, T. et al., J. Exp. Med. 175:983, 1992). Recent studies (Stollar, B. D., Mol. Immunol. 28: 1399, 1990; Valera, F. et al., Proc. Natl Acad. Sci. USA 88:5917, 1991; Algiman, M. et al., Proc. Natl. Acad. Sci. USA 89:3795, 1992; Kasaian, M. T. et al., J. Immunol. 148:2690, 1992; Rodman, T. C. et al., J. Exp. Med. 167:1228, 1988; Rodman, T. C. et al., Clin. Immunol. Immunopath. 57:430, 1990; Rodman, T. C. et al., Abstr. PoA 2429, VIII Internatl. Conf. AIDS, 1992; T. C. Rodman et al. submitted) however, have demonstrated a high order of epitopic specificity for certain sets of natural antibodies. Although no specific role or participation in immune mechanisms has been defined for any set, the proposition that natural antibodies may provide a "first line of defense" (Casali, P. et al., Ann Rev. Immunol. 7:513, 1989) against a new invader, while the forces of induced immune action are marshalled, is credible.
Acquired Immunodeficiency Syndrome (AIDS) is a disease which is characterized by a severe immune deficiency primarily caused by a decreased cell-mediated immune response (Gottlieb, M. et al., N. Engl. J. Med. 305:1425, 1981; Masur, J. et al., N. Engl. J. Med. 305:1431, 1981). The immunodeficiency state is characterized by a decrease in T helper lymphocytes (CD4.sup.+ cells), a reversal of the normal CD4 (T4)+:CD8 (T8)+ cell ratio, lymphopenia, an increased incidence of opportunistic infections (e.g., Pneumocystis carinii), and/or malignancy (e.g., lymphoma or Kaposis sarcoma). The syndrome is usually fatal.
The causative agent of AIDS is a retrovirus, now termed Human Immunodeficiency Virus (HIV) (also known as LAV/ARV/HTLV III) which infects T helper lymphocytes (Gallo, R. C. et al., Science 224:500, 1984; Barre-Sinoussi, F. et al., Science 220:868, 1983; Feorino, P. M. et al., Science 225:69, 1984; Levy, J. A. et al., Science 225:840, 1984). The CD4.sup.+ T-cell surface molecule has been identified as a receptor for the virus, and the virus' subsequent cytolytic activity depletes that cell population (Klatzman, D. et al., Nature 312:767, 1985; Dalgleish, A. G. et al., Nature 312:763, 1984; McDougal, J. S. et al., Science 231:382, 1986; Maddon, P. J. et al., Cell 47:333, 1986).
A patient is diagnosed with AIDS when he or she (1) tests positive for the presence of antibodies directed against HIV and presents with one or more of the specific indicator diseases (neoplasms, opportunistic infections) or (2) in the absence of laboratory evidence for HIV infection, all other causes of immunodeficiency are ruled out and one of the indicator diseases is present together with a low (less than 400/mm) CD4+ T lymphocyte count. AIDS-related complex (ARC) is a prodrome to AIDS and refers to those patients testing positive for HIV and presenting with persistent generalized lymphadenopathy, long-lasting fever, weight loss, persistent diarrhea, or extreme lassitude, but who have not yet developed one of the indicator diseases associated with full-blown AIDS.
U.S. patent application Ser. No. 07/924,412, discloses the presence of low affinity binding serum IgM antibodies immunoreactive with human protamines present in normal humans. These antibodies were detected upon observation of the curves of reactivity of IgM of normal, HIV negative sera with protamine (and peptides containing the immunoreactive epitope) at ascending antigen concentrations, wherein an increased rise in slope was found when assayed at higher antigen concentrations. The inference was made that the increase in rise of slope was a manifestation of the presence of a subset of antibodies with the same epitopic specificity as the principle subset, but of lower binding affinity. Review of the ontogenetic character of protamine led to the conclusion that the principle high affinity subset represented immunogenically induced antibodies and the low affinity subset were a set of natural antibodies. A formula was derived for measuring the difference in rise of slope of the curve for the 2 .mu.g/ml antigen and that for the 20 .mu.g/ml antigen: [(O.D. serum 1:100-O.D. serum 1:500) 20 .mu.g/ml]-[(O.D. serum 1:100-O.D. serum 1:500) 2 .mu.g/ml] or .DELTA.20-.DELTA.2, representing the proportionate titer of the low affinity binding IgM antibodies reactive with protamine. Calculation of .DELTA.20-.DELTA.2 for 60 HIV negative sera and 83 HIV positive sera showed that the values for 95% of the HIV positive sera were below the lower limit of the normal range, thus indicating that the low affinity subset of protamine reactive antibodies was selectively depleted in HIV positive sera, whereas the HIV positive (AIDS) serum, although displaying considerable protamine peptide reactivity, were more homogenous with respect to affinity. Therefore, it was concluded that a cohort of natural antibodies constituted a host factor of defense against HIV, maintaining a period of latency until, with failure of the immune system to develop an effective humoral arsenal against HIV and exhaustion of the pool of progenitors of natural antibodies, AIDS ensues.